The Structure of Polymer-Supported Triphenylphosphine Ditriflate: A Potentially Useful Reagent in Organic Synthesis Maria J. Petersson,† Ian D. Jenkins,*,† and Wendy A. Loughlin‡ Eskitis Institute for Cell and Molecular Therapies, Griffith UniVersity, Nathan, Brisbane, QLD 4111, Australia, and School of Biomolecular and Physical Sciences, Griffith UniVersity, Brisbane, QLD 4111, Australia
[email protected] ReceiVed February 26, 2008
FIGURE 1.
31
P NMR stack spectra (162 MHz) of the addition of Tf2O (0-4 equiv) to swollen, polymer-supported Ph3PO beads, 1, in CD2Cl2 at 25 °C (bottom to top): (a) 0, (b) 0.5, (c) 1.0, and (d) 4.0 equiv.
The structure of a polymer-supported version of the Hendrickson “POP” reagent, prepared by the reaction of polymersupported triphenylphosphine oxide 1 with triflic anhydride, is established as an equilibrium mixture of polymer-supported triphenylphosphine ditriflate 3 (δ 79.4 ppm) and polymersupported phosphonium anhydride 4 (δ 73.3 ppm). The 31P NMR chemical shift reported previously for 3 is shown to be incorrect. The Hendrickson “POP” reagent1,2 (triphenylphosphonium anhydride trifluoromethanesulfonate, or bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate 6) brings about dehydrations and coupling reactions (such as ester and amide formation), in a similar manner to the Mitsunobu reaction3–6 through what appears to be the same intermediate (an alkoxyphosphonium salt). In previous work,7,8 it was shown that a polymer-supported † Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan. ‡ Eskitis Institute and School of Biomolecular and Physical Sciences, Griffith University. (1) Hendrickson, J. B. In Encyclopaedia of Reagents for Organic Synthesis; Paquette, L. A. Ed.; Wiley: New York, 1995; Vol. 8, pp 5404-5407. (2) (a) Hendrickson, J. B.; Hussoin, M. S. J. Org. Chem. 1987, 52, 4137– 4139. (b) Hendrickson, J. B.; Hussoin, M. S. J. Org. Chem. 1989, 54, 11441149. (3) Mitsunobu, O. Synthesis 1981, 1–28. (4) Hughes, D. L. Org. React. 1992, 42, 335–656. (5) Jenkins, I. D.; Mitsunobu, O. In Encyclopaedia of Reagents for Organic Synthesis; Paquette, L. A. Ed.; Wiley: New York, 1995; Vol. 8, pp. 53795390. (6) Hughes, D. L. Org. Prep. Proced. Int. 1996, 28, 127–164. (7) Elson, K. E.; Jenkins, I. D.; Loughlin, W. A. Tetrahedron Lett. 2004, 45, 2491–2493. (8) Fairfull-Smith (nee´ Elson) , K. E.; Jenkins, I. D.; Loughlin, W. A. Org. Biomol. Chem. 2004, 2, 1979–1986.
10.1021/jo800447v CCC: $40.75 2008 American Chemical Society Published on Web 05/23/2008
version of this reagent could be readily prepared by reaction of the corresponding polymer-supported phosphine oxide with triflic anhydride (Tf2O). This reagent has the advantage over the Hendrickson reagent that, unlike triphenylphosphine oxide (Ph3PO), it is easily removed from the reaction product by simple filtration of the polymer beads. Moreover, it can be recycled and reused without loss of efficiency. The reagent is particularly useful in medicinal chemistry for the direct synthesis of sulfonamides from sulfonic acids and amines,9 and since 2007, the precursor to the reagent, polymer-supported Ph3PO, has been commercially available. We believe that this reagent has considerable potential in organic synthesis as a very powerful but mild dehydrating/activating agent. For example, it should prove useful as an alternative to the Hendrickson reagent for the synthesis of heterocycles such as oxazolines, thiazolines, and imidazolines.10 On the basis of 31P NMR and other data, the structure of this polymer-supported reagent was assigned as 3 (where the majority of phosphoryl groups on the polymer bead were in the form of the ditriflate). However, characterization of 3 proved difficult due to its extreme sensitivity to moisture. Here, we provide evidence that the actual dehydrating reagent consists of a mixture of polymer-supported triphenylphosphine ditriflate 3 and polymer-supported triphenylphosphonium anhydride trifluoromethanesulfonate 4. Addition of freshly distilled Tf2O (0.5 equiv) to an NMR tube of swollen, dried, polymer-supported Ph3PO 1 in CD2Cl2 under nitrogen resulted in two peaks in the gel-phase 31P NMR spectrum at δ 52.9 and 73.3 ppm, respectively (Figure 1b). When 1 was treated with 1.0 equiv of Tf2O, the peak at δ 52.9 ppm was not observed. The original peak at δ 73.3 was still present, but in addition, a new peak appeared at δ 79.4 ppm (9) Caddick, S.; Wilden, J. D.; Judd, D. B. J. Am. Chem. Soc. 2004, 126, 1024–1025. (10) (a) You, S.-L.; Kelly, J. W. J. Org. Chem. 2003, 68, 9506–9509. (b) You, S.-L.; Kelly, J. W. Org. Lett. 2004, 6, 1681-1683. (c) You, S.-L.; Kelly, J. W. Tetrahedron Lett. 2005, 46, 2567-2570. (d) You, S.-L.; Kelly, J. W. Tetrahedron, 2005, 61, 241-249.
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SCHEME 1.
Formation of Polymer-Supported Reagent 3 a 4
(Figure 1c). The spectrum was unchanged after standing for 24 h. The relative intensity of the peak at δ 79.4 ppm increased as the Tf2O was increased from 1 to 4 equiv (Figure 1d). In the 0.5 equiv experiment, there is partial formation of the ditriflate 3. Some of the phosphonium ditriflate [Ph2P(OTf)2] groups undergo further reaction with neighboring diphenylphosphoryl (Ph2PO) groups on the polymer backbone to give anhydride (P-O-P) 4 (δ 73.3 ppm). However, such anhydride formation is presumably not possible for all Ph2P(OTf)2 groups on 3, as not all would have a neighboring Ph2PO group, and some would be more hindered or less accessible. This would mean that there should be three phosphorus species present, Ph2P(OTf)2 and Ph2PO as shown in 3 and P-O-P as shown in 4. We suggest that all three of these species are in equilibrium (Scheme 1). In the case of Ph2PO (δ 26.8 ppm) and Ph2P(OTf)2 (δ 79.4 ppm), the equilibrium (represented by 1 a 3) must be fast (on the 31P NMR time scale) to give a time-averaged peak at δ 52.9 ppm (very close to the calculated value of δ 53.1), whereas the equilibrium between 3 and 4 must be slow (on the 31P NMR time scale) so that a separate signal is seen for the P-O-P species 4. As expected, the gel-phase 31P NMR signal for 4 (δ 73.3 ppm) is close to that of the solution-phase Hendrickson reagent 6 (δ 75.6 ppm).11 The fact that the equilibrium between 1 and 3 is fast whereas that between 3 and 4 is slow (on the 31P NMR time scale) is not surprising as the former involves a solution phase reagent (Tf2O) interacting with Ph2PO groups on the polymer, while the latter involves a gel-phase reaction where the relative movement of the phosphoryl groups is restricted by the (insoluble) cross-linked polymer network. In the 1.0 equiv experiment (Figure 1c), there is sufficient Tf2O to react with all of the Ph2PO groups in 1, so that only the ditriflate (3) and anhydride (P-O-P) species 4 are observed. With excess Tf2O (4 equiv), the equilibrium shifts in favor of the ditriflate 3. (11) Crich, D.; Dyker, H. Tetrahedron Lett. 1989, 30, 475–476.
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It should be noted that there may be a contribution to the δ 52.9 ppm peak from the protonated polymer-supported Ph3PO 2, as a result of hydrolysis of some of the Tf2O by adventitious moisture. Thus, treatment of 1 (δ 26.8 ppm) with 0.5, 1.0, and 2.0 equiv of triflic acid gave signals at δ 42.8 ppm (0.5 equiv), δ 52.5 ppm (1.0 equiv), and δ 56.0 ppm (2.0 equiv), respectively. Given the precautions taken in these experiments (Figure 1), and their reproducibility, this contribution should be minor. However, adventitious moisture may explain the previously reported 31P NMR shift for 3 of δ 53.3 ppm.4 Treatment of the polymer-supported reagent (3 a 4, generated as before) with water (2 drops) resulted in immediate replacement of the peaks at δ 73.3 and 79.4 ppm by a peak at δ 38.2 ppm. This is consistent with hydrolysis to give a mixture of the starting material 1 (δ 26.8 ppm) in rapid equilibrium with the protonated phosphine oxide 2 (δ 52.5 ppm). To provide further support for these assignments and equilibria, Ph3PO (0.5 equiv relative to 1) was added to the polymersupported reagent (3 a 4, generated as before). 31P NMR signals were generated at δ 79.4, 75.6, and 52.9 ppm (relative amounts ca. 9:12:1). When 1.0 equiv of Ph3PO was used, only the peaks at δ 75.6 and 52.9 ppm (ca. 5:2) remained. With excess Ph3PO (4 equiv), a single peak at δ 40.7 ppm was observed. A small amount of Ph3PO (0.5 equiv) would be expected to react preferentially with the anhydride 4 to give the mixed anhydride 5 [reaction with Ph2P(OTf)2 groups in 3 would be slower as these groups were the ones that failed to form anhydride linkages previously, as a result of being more hindered or less accessible, therefore the 31P NMR signal for 3 (δ 79.4 ppm) would remain]. The mixed anhydride 5 can undergo further reaction with Ph3PO to give the Hendrickson reagent 6 (together with starting material 1), or alternatively, a rapid (null) exchange reaction to give back 5. This latter process would result in a time-averaged 31P NMR signal of approximately δ 53 ppm arising from the Ph3PO (δ 29.1 ppm),12 polymer-supported Ph3PO 1 (δ 26.8 ppm), and the “outer” phosphorus atom in 5 (ca. δ 75.6 ppm). Conversely, the “inner” phosphorus atom in 5 (the one attached directly to the polymer backbone) would not be subject to time-averaging and would therefore give a 31P NMR signal of approximately δ 75 ppm (any conversion 5 f 4 would be expected to be slow on the 31P NMR time scale by analogy with the equilibrium between 3 and 4, while reaction between the two polymer beads 1 and 5 would be expected to be extremely slow). With excess Ph3PO (4 equiv), there would be negligible 5 present and the 31P NMR signal would be dominated by the exchange between 6 and Ph3PO (i.e., the peak at δ 40.7 ppm). It should also be noted that formation of the “POP” bond in 4 could be between separate polymer beads, or between phosphoryl groups on the same polymer bead. As the polymer loading is quite high (∼3 mmol P/g of polymer, corresponding to almost 80% of the phenyl groups of the polystyrene backbone bearing a diphenylphosphoryl moiety), it might be expected that formation of a POP bond between adjacent phosphoryl groups on the same polymer bead, possibly to give a [3.3]paracyclophane-like structure 7, would be most likely. The structure 7 would be expected to be more strained than [3.3]paracyclophane13 itself due to the additional substituents on the ring and (12) Elson, K. E.; Jenkins, I. D.; Loughlin, W. A. Org. Biomol. Chem. 2003, 1, 2958–2965. (13) See: Longone, D T.; Kusefoglu, S. H.; Gladysz, J. A. J. Org. Chem. 1977, 42, 2787–2788, and references cited therein.
the fact that the POP linkage prefers to be linear.14 However, examples of cyclic P-O-P compounds (such as 8 and 9) where the P-O-P linkages cannot be linear are known.15 As the concentration of phosphoryl groups within the swollen polymer bead is quite high, much larger rings containing P-O-P linkages could also be formed between phosphoryl groups in close proximity. Conversely, the likelihood of P-O-P formation between polymer beads seems much less likely given that these are insoluble polymer particles of the order of 0.05 mm in diameter. On a molecular scale, the polymer beads are huge and therefore their surface area is quite small.
In conclusion, these experiments provide evidence that the structure of the polymer-supported version of the Hendrickson “POP” reagent is an equilibrium mixture of polymer-supported triphenylphosphine ditriflate 3 (δ 79.4 ppm) and polymersupported phosphonium anhydride 4 (δ 73.3 ppm). Or, more precisely, the polymer beads contain a mixture of Ph2P(OTf)2 and P-O-P groups. The ditriflate becomes the dominant structure only in the presence of excess Tf2O. The fact that the structure consists of an equilibrium mixture of two distinct species does not appear to interfere with its use as a potent dehydrating agent.7–9 Experimental Section
Finally, it is interesting to note that the only product formed when Ph3PO is treated with excess Tf2O is the Hendrickson reagent 6. Triphenylphosphine ditriflate is not observed. Such a species becomes possible, however, with polymer-supported Ph3PO, where some of the phosphoryl groups are relatively inaccessible to attack by a second phosphoryl group, or where the formation of a POP species involves considerable ring strain. (14) Aaberg, A.; Gramstead, T.; Husebye, S. Acta Chem. Scand. 1980, A34, 717–724. (15) Elson, K. E.; Jenkins, I. D.; Loughlin, W. A. Aust. J. Chem. 2004, 57, 371–376.
Polymer-supported Ph3PO, 1, was prepared as described previously,8 and dried under vacuum at 125 °C for 2 days, using a Kugelrohr oven. 31P NMR spectra were determined at 162 MHz. In a typical procedure, the polymer beads were dried under high vacuum for 48 h prior to use. In a 5 mm NMR tube, dry polymer-supported Ph3PO (75 mg, 0.23 mmol, 3 mmol/g) was allowed to swell in CD2Cl2 (750 µL) for 0.5 h to generate a gel-phase sample. Tf2O (39 µL, 0.23 mmol) was added and the slurry mixed for 0.5 h. The 31P NMR spectrum was then recorded at 25 °C.
Acknowledgement. Financial support for this work was provided by Griffith University, and the Eskitis Institute for Cell and Molecular Therapies, Griffith University. We thank a referee for constructive comments and Dr. Ezio Rizzardo of the CSIRO for useful discussions. JO800447V
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